Protease-activated receptors (PARs) are a family of G protein-coupled receptors activated by the proteolytic cleavage of their N-terminal extracellular domain, exposing a new amino terminal sequence that functions as a tethered ligand to activate the receptors. (Zania et. al., J Pharmacol Exp Ther. 2006 July; 318(1):246-54). Four different PARs have been identified as PAR1, PAR2, PAR3 and PAR4, responding to a group of serine proteases. Modulation of PAR1-mediated signaling activities has several therapeutic applications. Interest in PAR-1 was initiated from its involvement in thrombin-induced activation of platelets. Subsequently, PAR-1 activation was found to mediate several processes in vascular biology, inflammation, malignancy, and tissue remodeling in normal development. Inhibition of PAR1 is helpful for treating thrombotic and vascular proliferative disorders as well as for inhibiting progression of cancers. PAR1 has been shown to be involved in a variety of primary human cancers including those of breast, colon, prostate, ovary and melanoma. (Zania et. al., 246-54; Wilson et. al., Cancer Res 2009, 69(7), 3188-3194; Gao et. al., Biol. Chem. 2010, 391, 803-812; Trivedi et. al., Cell 2009, 137(2), 332-343; Borensztajn et. al., Thrombosis Research 2009, 124, 219-225; Day et. al., J Thorac Cardiovasc Surg. 2006, 131, 21-7; Cunningham et. al., J. Exp. Med. 2000, 191, 455-62; Niessen et. al., Nature, 2008, 452, 654-658; Bar-Shavit et. al., US 20090215683; Perez et. al., US 20090176803; Hirano et. al., US 20100063048; Mackman et. al., US 20090022729; Teng et. al., US 20020004518).
Platelets are key mediators of thrombosis. Drugs that interfere with platelet activation substantially improve survival in arterial thrombotic disease. (Dowal et. al., Current Vascular Pharmacology, 2010, 8, 140-154). In the case of thrombus formation, the activation of platelets is initiated through the thrombin receptor pathway. The SFLLRN peptide activates platelets through PAR1. Upon activation, the platelets undergo many changes induced by multiple signaling cascades. One downstream effect of activation is the secretion of granules, which then potentiates platelet functions in controlling bleeding. Granule secretion also contributes to the growth of thrombi.
Several categories of antiplatelet agents are presently under development including those directed at platelet adhesion proteins, those directed at signaling proteins, and those directed at ligand binding sites on GPCRs. Another strategy for developing improved antiplatelet reagents directed at GPCRs is to develop drugs that act via mechanisms other than competitive antagonism at the ligand binding site. Allosteric modulators can bind GPCRs outside of the ligand binding site and induce a conformational change in the receptor. Pharmacological properties of such modulators suggest that they may have favorable therapeutic indices and increased specificity compared with competitive antagonists. In addition, reagents that target intracellular loops of GPCRs have been developed and may prove to be useful reagents for modulating GPCR signaling. (Dowal et al.).
Nishida et al. discloses morpholine compounds as factor IXa inhibitors and for the treatment of blood coagulation. (WO 2010/065717). Bauer et al. discloses a series of menthol substituted antithrombotic agents. (WO 2003/080564). Folkes et al. discloses a group of inhibitors of plasminogen activator inhibitor-1 for the treatment of thrombotic disorders. (GB 2372986, 2002). Beight et al., discloses dibenzoylbenzediamines as antithrombotic agents. (WO 1999/00127).
Jeffrey et al., discloses benzamide derivatives as allosteric modulators for the treatment of neurological and psychiatric disorders. (WO 2008/151184 A1). Zhou et al. discloses the use of a group of diaminophenyl derivatives for the treatment of pain, anxiety, depression, cocaine addiction and fragile X-syndrome. (Bioorg Med Chem Lett. 2009, 19(23):6502-6). Platelets represent a good cellular target for pharmacological manipulation via allosteric modulation. One of the problems in developing an antiplatelet agent is achieving a potent antiplatelet effect while avoiding hemorrhagic complications. Development of allosteric modulators of platelet function could limit bleeding complications associated with many current antiplatelet agents.